Combination therapy with zoledronic acid and cetuximab effectively suppresses growth of colorectal cancer cells regardless of KRAS status.

Targeted molecular therapy is an effective anticancer strategy. Anti-EGFR monoclonal antibodies such as cetuximab (CTX) have been approved for the treatment of various malignancies, including colorectal cancer (CRC) with wild-type KRAS. However, their efficacy in patients with KRAS mutations has not been established. Therefore, we investigated whether CTX treatment was effective as a single agent or in combination with zoledronic acid (ZOL) in human CRC cell lines with different KRAS status. CRC cell lines SW48 (wild-type KRAS) and LS174T (mutant KRAS) were treated with ZOL, CTX and a combination of both drugs. Cytotoxicity was measured using the MTT assay. Changes in the levels of intracellular signaling proteins were evaluated using western blot analysis. Finally, we evaluated the efficacy of the combination treatment in an in vivo xenograft model. We observed that ZOL apparently inhibited growth in both cell lines, whereas CTX showed little effect. ZOL also increased the levels of unprenylated RAS. Combined ZOL and CTX treatment was synergistic in both cell lines and was associated with inhibition of the RAS-MAPK and AKT-mTOR signaling pathways. Furthermore, the combination treatment was more effective in suppressing the growth of xenografts derived from both SW48 and LS174T cells; this effect was associated with increased apoptosis. These results demonstrate that ZOL inhibits the growth of colon cancer cells regardless of KRAS status, and combination therapy using ZOL and CTX enhances this growth suppression. These findings suggest a novel strategy for the treatment of CRC independent of KRAS mutational status.

Clinical significance of glycoprotein nonmetastatic B and its association with HER2 in breast cancer.

Glycoprotein nonmetastatic B (GPNMB) is a potential oncogene that is particularly expressed in melanoma and breast cancer (BC). To clarify its clinical significance in BC, we measured serum GPNMB in vivo and investigated its cross talk with human epidermal growth factor 2 (HER2). GPNMB was expressed in four of six breast cell lines (SK-BR-3, BT-474, MDA-MD-231, and MDA-MD-157), two of six colorectal cell lines, and two of four gastric cancer (GC) cell lines. We established a GPNMB quantification system using enzyme-linked immunosorbent assay (ELISA) for these cell lines. We measured serum GPNMB in vivo in 162 consecutive BC patients and in 88 controls (50 colorectal cancer [CC] and 38 GC patients). The GPNMB concentration in BC, CC and GC was 8.163, 5.751 and 6.55 ng/mL, respectively. The GPNMB level was significantly higher in BC patients than in CC patients (P = 0.021). The HER2-rich subtype of BC patients had significantly higher GPNMB levels than other subtypes (vs. Luminal; P = 0.038; vs. DCIS; P = 0.0195). These high GPNMB levels decreased after treatment (surgery/chemotherapy). Next, we examined the relationship between GPNMB and HER2 in vitro using SK-BR3 and BT-474 (HER2-positive/GPNMB-positive) cells. GPNMB depletion by small interfering RNA (siRNA) increased both HER2 expression and phosphorylation. Trastuzumab (Tra) in combination with docetaxel promoted cell growth inhibition, and treatment with Tra or an Extracellular signal-related kinase (ERK) inhibitor enhanced GPNMB expression. These results indicate that GPNMB might be a surrogate marker for BC and may cross talk with the HER2 signal pathway. GPNMB may therefore emerge as an important player in anti-HER2 therapy.

Prediction of macrometastasis in axillary lymph nodes of patients with invasive breast cancer and the utility of the SUV lymph node/tumor ratio using FDG-PET/CT.

BACKGROUND: Axillary lymph node dissection (ALND) is important for improving the prognosis of patients with node-positive breast cancer. However, ALND can be avoided in select micrometastatic cases, preventing complications such as lymphedema or paresthesia of the upper limb. To appropriately omit ALND from treatment, evaluation of the axillary tumor burden is critical. The present study evaluated a method for preoperative quantification of axillary lymph node metastasis using positron emission tomography/computed tomography (PET/CT). METHODS: The records of breast cancer patients who received radical surgery at the Gifu University Hospital (Gifu, Japan) between 2009 and 2014 were reviewed. The axillary lymph nodes were preoperatively evaluated by PET/CT. Lymph nodes were dissected by sentinel lymph node biopsy (SLNB) or ALND and were histologically diagnosed by experienced pathologists. The maximum standardized uptake value (SUVmax) was measured in both the axillary lymph node (SUV-LN) and primary tumor (SUV-T). The SUV-LN/T ratio (NT ratio) was calculated by dividing the SUV-LN by the SUV-T, and the efficacies of the NT ratio and SUV-LN were compared using receiver operating characteristic (ROC) curve analysis. The diagnostic performance was also compared between the techniques with the McNemar test. RESULTS: A total of 171 operable invasive breast cancer patients were enrolled, comprising 69 node-positive patients (macrometastasis (Mac): n = 55; micrometastasis (Mic): n = 14) and 102 node-negative patients (Neg). The NT ratio for node-positive patients was significantly higher than in node-negative patients (0.5 vs. 0.316, respectively, P = 0.041). The NT ratio for Mac patients (0.571) was significantly higher than in Mic (0.227) and Neg (0.316) patients (P <0.01 and P = 0.021, respectively). The areas under the curves (AUCs) by ROC analysis for the NT ratio and SUV-LN were 0.647 and 0.811, respectively (P <0.01). In patients with an SUV-T ≥2.5, the modified AUCs for the NT ratio and SUV-LV were 0.757 and 0.797 (not significant). CONCLUSION: The NT ratio and SUV-LN are significantly higher in patients with axillary macrometastasis than in those with micrometastasis or no metastasis. The NT ratio and SUV-LN can help quantify axillary lymph node metastasis and may assist in macrometastasis identification, particularly in patients with an SUV-T ≥2.5.

Novel navigation surgery using image fusion of PET/CT and sonography for axillary neoplasm: First experience.

INTRODUCTION: Ultrasound sonography (US)-guided navigation systems are widely used in various organs, including the breast and liver, to locate precisely lesions that are difficult to palpate or isolate after being identified by other imaging techniques. A recent new method, "volume navigation" (Vnav), delivers real-time image fusion of US with other modalities such as MRI, CT, and PET/CT to facilitate identification and excision of suspected pathology. PRESENTATION OF CASE: The present report describes a novel navigation technique using Vnav-PET/CT, which delivers image fusion of US with PET/CT. To identify the axillary targets using Vnav-PET/CT, we set at least two landmarks then injected 0.2ml viscous blue dye in and around the capsule, which resulted in precise resection. Case 1: A 53-year-old woman with 2 PET/CT-positive lymph nodes in the right axilla underwent easy identification of the targets using the navigation technique followed by lymph node dissection. Among 32 lymph nodes dissected, only the two lymph nodes stained by blue dye were shown histologically to be malignant. Case 2: A 68-year-old woman had a PET/CT-positive lymph node in the left axilla. Vnav-PET/CT easily identified the target, which was successfully dissected under local anaesthesia. DISCUSSION: This navigation and marking using Vnav-PET/CT helped us easily approach the target, resulted in less surgical time, and avoided unsatisfactory axillary complications. These advances of the navigation system enable us to perform precise minimally invasive surgery. CONCLUSION: This is the first report of navigation surgery using Vnav-PET/CT, which may assist minimally invasive procedures, especially in the axilla.

[A case of advanced colon cancer with metastases to both supraclavicular and para-aortic lymph nodes effectively treated by radiation and S-1 therapy].

We report the case of a 60-year-old woman with multiple lymph node metastases after ascending colon cancer who received radiation therapy and then chemotherapy with S-1. She was diagnosed with lymph node metastasis of the para aorta and left upper clavicle 10 months after surgery. We performed radiation therapy for the left upper clavicle (64 Gy)and para aorta (40 Gy). Consequently, we administered S-1(100mg/day)orally. After three months, the upper clavicle lymph nodes had disappeared and the para-aortic lymph nodes reduced. All metastatic lesions disappeared after 10 months. She survived for 32 months after the radiation therapy.

[Three cases of gastric cancer with para-aortic lymph node metastases succesfully treated by S-1/CDDP combination therapy followed by curative resection].

Due to advanced gastric cancer with abdominal para-aortic lymph node metastases, we performed a curative operation in three cases in which S-1/CDDP combination therapy proved effective. In case 1, after only one course of this chemotherapy, the reduction of the primary lesion was slight, but para-aortic metastatic lymph nodes were remarkably reduced. We performed a curative operation with complete D3 lymph node dissection. In case 2, after two courses the reduction of the primary lesion was remarkable, and para-aortic metastatic lymph nodes almost disappeared. Therefore, we performed a curative operation with D2 lymph node dissection. In case 3, after two courses the reduction of the primary lesion was cicatrized. Although para-aortic metastatic lymph nodes were gradually reduced, one of them increased after the third period of treatment. Therefore, we performed a curative operation with complete D2 lymph node dissection and 16b1 lateral lymph node dissection. All underwent postoperative adjuvant chemotherapy, and have been surviving for 58 months, 42 months, and 18 months, respectively. In advanced gastric cancer with para-aortic lymph node metastases without other non-curative factors, long-term survival can be expected by combining a curative operation with S-1/CDDP combined therapy.